tbuckley/cabot-search huggingface dataset:
Effect of Conventional Lifestyle Interventions on Type 2 Diabetes Incidence by Glucose-Defined Prediabetes Phenotype: An Individual Participant Data Meta-analysis of Randomized Controlled Trials
Authors: Thirunavukkarasu Sathish, Kamlesh Khunti, K.M. Venkat Narayan, Viswanathan Mohan, Melanie J. Davies, Thomas Yates, Brian Oldenburg, Kavumpurathu R. Thankappan, Robyn J. Tapp, Ram Bajpai, Ranjit Mohan Anjana, Mary B. Weber, Mohammed K. Ali, Jonathan E. Shaw
Journal: Diabetes Care (2023)

OBJECTIVE To examine whether the effect of conventional lifestyle interventions on type 2 diabetes incidence differs by glucose-defined prediabetes phenotype. RESEARCH DESIGN AND METHODS We searched multiple databases until 1 April 2023 for randomized controlled trials that recruited people with isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), and impaired fasting glucose plus impaired glucose tolerance (IFG+IGT). Individual participant data were pooled from relevant trials and analyzed through random-effects models with use of the within-trial interactions approach. RESULTS Four trials with 2,794 participants (mean age 53.0 years, 60.7% men) were included: 1,240 (44.4%), 796 (28.5%), and 758 (27.1%) had i-IFG, i-IGT, and IFG+IGT, respectively. After a median of 2.5 years, the pooled hazard ratio for diabetes incidence in i-IFG was 0.97 (95% CI 0.66, 1.44), i-IGT 0.65 (0.44, 0.96), and IFG+IGT 0.51 (0.38, 0.68; Pinteraction = 0.01). CONCLUSIONS Conventional lifestyle interventions reduced diabetes incidence in people with IGT (with or without IFG) but not in those with i-IFG.
Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa
Authors: Andreea Petrasca, Roisin Hambly, Niamh Kearney, Conor M Smith, Emily K Pender, Julie Mac Mahon, Aoife M O’Rourke, Mohamed Ismaiel, Patrick A Boland, Jose P Almeida, Czara Kennedy, Alexandra Zaborowski, Siun Murphy, Desmond Winter, Brian Kirby, Jean M Fletcher
Journal: British Journal of Dermatology (2023)

Abstract Background Targeting immunometabolism has shown promise in treating autoimmune and inflammatory conditions. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving painful lesions in apocrine gland-bearing skin. Therapeutic options for HS are limited and often ineffective; thus, there is a pressing need for improved treatments. To date, metabolic dysregulation has not been investigated in HS. As HS is highly inflammatory, we hypothesized that energy metabolism is dysregulated in these patients. Metformin, an antidiabetic drug, which is known to impact on cellular metabolic and signalling pathways, has been shown to have anti-inflammatory effects in cancer and arthritis. While metformin is not licensed for use in HS, patients with HS taking metformin show improved clinical symptoms. Objective To assess the effect and mechanism of action of metformin in HS. Methods To assess the effect of metformin in vivo, we compared the immune and metabolic profiles of peripheral blood mononuclear cells (PBMCs) of patients with HS taking metformin vs. those not taking metformin. To examine the effect of metformin treatment ex vivo, we employed a skin explant model on skin biopsies from patients with HS not taking metformin, which we cultured with metformin overnight. We used enzyme-linked immunosorbent assays, multiplex cytokine assays and quantitative real-time polymerase chain reaction (RT-PCR) to measure inflammatory markers, and Seahorse flux technology and quantitative RT-PCR to assess glucose metabolism. Results We showed that metabolic pathways are dysregulated in the PBMCs of patients with HS vs. healthy individuals. In metformin-treated patients, these metabolic pathways were restored and their PBMCs had reduced inflammatory markers following long-term metformin treatment. In the skin explant model, we found that overnight culture with metformin reduced inflammatory cytokines and chemokines and glycolytic genes in lesions and tracts of patients with HS. Using in vitro assays, we found that metformin may induce these changes via the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway, which is linked to glycolysis and protein synthesis. Conclusions Our study provides insight into the mechanisms of action of metformin in HS. The anti-inflammatory effects of metformin support its use as a therapeutic agent in HS, while its effects on immunometabolism suggest that targeting metabolism is a promising therapeutic option in inflammatory diseases, including HS.
SARS-CoV-2 Infection, Hospitalization, and Mortality in Adults With and Without Cancer
Authors: Seyed M. Hosseini-Moghaddam, Frances A. Shepherd, Sarah Swayze, Jeffrey C. Kwong, Kelvin K. W. Chan
Journal: JAMA Network Open (2023)

Patients with cancer are at increased risk of SARS-CoV-2-associated adverse outcomes.To determine the associations of tumor type with SARS-CoV-2 infection, hospitalization, intensive care unit (ICU) admission, and death.This retrospective, population-based cohort study included community-dwelling adults aged at least 18 years in Ontario, Canada, ICES-linked provincial health databases from January 1, 2020, to November 30, 2021. Data were analyzed from December 1, 2021, to November 1, 2022.Cancer diagnosis.The primary outcome was SARS-CoV-2 infection, and secondary outcomes included all-cause 14-day hospitalization, 21-day ICU admission, and 28-day death following SARS-CoV-2 infection. Cox proportional hazards models were used to obtain adjusted hazard ratios (aHRs) and 95% CIs.Of 11 732 108 people in the ICES-linked health databases, 279 287 had cancer (57.2% female; mean [SD] age, 65.9 [16.1] years) and 11 452 821 people did not have cancer (45.7% female; mean [SD] age, 65.9 [16.0] years). Overall, 464 574 individuals (4.1%) developed SARS-CoV-2 infection. Individuals with hematologic malignant neoplasms (33 901 individuals) were at increased risk of SARS-CoV-2 infection (aHR, 1.19; 95% CI, 1.13-1.25), 14-day hospitalization (aHR, 1.75; 95% CI, 1.57-1.96), and 28-day mortality (aHR, 2.03; 95% CI, 1.74-2.38) compared with the overall population, while individuals with solid tumors (245 386 individuals) were at lower risk of SARS-CoV-2 infection (aHR, 0.93; 95% CI, 0.91-0.95) but increased risk of 14-day hospitalization (aHR, 1.11; 95% CI, 1.05-1.18) and 28-day mortality (aHR, 1.31; 95% CI, 1.19-1.44). The 28-day mortality rate was high in hospitalized patients with hematologic malignant neoplasms (163 of 321 hospitalized patients [50.7%]) or solid tumors (486 of 1060 hospitalized patients [45.8%]). However, the risk of 21-day ICU admission in patients with hematologic malignant neoplasms (aHR, 1.14; 95% CI, 0.93-1.40) or solid tumors (aHR, 0.93; 95% CI, 0.82-1.05) was not significantly different from that among individuals without cancer. The SARS-CoV-2 infection risk decreased stepwise with increasing numbers of COVID-19 vaccine doses received (1 dose: aHR, 0.63; 95% CI, 0.62-0.63; 2 doses: aHR, 0.16; 95% CI, 0.16-0.16; 3 doses: aHR, 0.05; 95% CI, 0.04-0.06).These findings highlight the importance of prioritization strategies regarding ICU access to reduce the mortality risk in increased-risk populations, such as patients with cancer.
Project Optimus: Is the US Food and Drug Administration Waiving Dose Optimization for Orphan Drugs?
Authors: Austin Wesevich, Mark J. Ratain
Journal: JAMA Oncology (2023)

This Viewpoint discusses the US Food and Drug Administration’s Project Optimus, which focuses on new oncology drug dose optimization and examines concerns about the accelerated postmarketing approval of adjusted dosing of oncologic drugs.
PEG2000-PLA-based nanoscale polymeric micelles reduce paclitaxel-related toxicity in beagle dogs
Authors: Jun Lu, Bo Han, Bo Zhang, Benkun Zou, Minjuan Hu, Hongyu Liu, Chao Zhou, Fangfei Qian, Shuyuan Wang, Yanwei Zhang, Yuqing Lou, Tianqing Chu, Jingsong Zhou, Baohui Han, Hua Zhong
Journal: Journal of Controlled Release (2023)
Use of Expedited Regulatory Programs and Clinical Development Times for FDA-Approved Novel Therapeutics
Authors: Alissa K. Wong, Maryam Mooghali, Reshma Ramachandran, Joseph S. Ross, Joshua D. Wallach
Journal: JAMA Network Open (2023)

This cross-sectional study evaluates the duration between application to US Food and Drug Administration (FDA) and approval for new drugs and biologics in the US from 2015 to 2022.
War and Health Care Services Utilization for Chronic Diseases in Rural and Semiurban Areas of Tigray, Ethiopia
Authors: Tesfay Gebregzabher Gebrehiwet, Haftom Temesgen Abebe, Abraha Woldemichael, Kibrom Gebresilassie, Mache Tsadik, Akeza Awealom Asgedom, Girmatsion Fisseha, Kiros Berhane, Aregawi Gebreyesus, Yibrah Alemayoh, Measho Gebresilassie, Hagos Godefay, Hailay Abrha Gesesew, Solomon Tesfaye, Elias S. Siraj, Maru W. Aregawi, Afework Mulugeta
Journal: JAMA Network Open (2023)

Importance The war in Tigray, Ethiopia, has disrupted the health care system of the region. However, its association with health care services disruption for chronic diseases has not been well documented. Objective To assess the association of the war with the utilization of health care services for patients with chronic diseases. Design, Setting, and Participants Of 135 primary health care facilities, a registry-based cross-sectional study was conducted on 44 rural and semiurban facilities of Tigray. Data on health services utilization were extracted for patients with tuberculosis, HIV, diabetes, hypertension, and psychiatric disorders in the prewar period (September 1, to October 31, 2020) and during the first phase of the war period (November 4, 2020, to June 30, 2021). Main Outcomes and Measures Records on the number of follow-up, laboratory tests, and patients undergoing treatment of the aforementioned chronic diseases were counted during the prewar and war periods. Results Of 4645 records of patients with chronic diseases undergoing treatment during the prewar period, 998 records (21%) indicated having treatment during the war period. Compared with the prewar period, 59 of 180 individuals (33%; 95% CI, 26%-40%) had tuberculosis, 522 of 2211 (24%; 95% CI, 22%-26%) had HIV, 228 of 1195 (19%; 95% CI, 17%-21%) had hypertension, 123 of 632 (20%; 95% CI, 16%-22%) had psychiatric disorders, and 66 of 427 (15%; 95% CI, 12%-18%) had type 2 diabetes records, which revealed continued treatment during the war period. Of 174 records of patients with type 1 diabetes in the prewar period, at 2 to 3 months into the war, the numbers dropped to 10 with 94% decline compared with prewar observations. Conclusions and Relevance This study found that the war in Tigray has resulted in critical health care service disruption and high loss to follow-up for patients with chronic disease, likely leading to increased morbidity and mortality. Local, national, and global policymakers must understand the extent and impact of the service disruption and urge their efforts toward restoration of those services.
Coding Error in Study Evaluating Eligibility of US Black Women Under USPSTF Lung Cancer Screening Guidelines
Authors: Alexandra L. Potter, Chi-Fu Jeffrey Yang, Julie R. Palmer
Journal: JAMA Oncology (2023)

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Anti–SARS-CoV-2 Pharmacotherapies Among Nonhospitalized US Veterans, January 2022 to January 2023
Authors: Lei Yan, Elani Streja, Yuli Li, Nallakkandi Rajeevan, Mazhgan Rowneki, Kristin Berry, Denise M. Hynes, Francesca Cunningham, Grant D. Huang, Mihaela Aslan, George N. Ioannou, Kristina L. Bajema
Journal: JAMA Network Open (2023)

Importance Several pharmacotherapies have been authorized to treat nonhospitalized persons with symptomatic COVID-19. Longitudinal information on the use of these therapies is needed. Objective To analyze trends and factors associated with prescription of outpatient COVID-19 pharmacotherapies within the Veterans Health Administration (VHA). Design, Setting, and Participants This cohort study evaluated nonhospitalized veterans in VHA care who tested positive for SARS-CoV-2 from January 2022 through January 2023 using VHA and linked Community Care and Medicare databases. Exposures Demographic characteristics, underlying medical conditions, COVID-19 vaccination, and regional and local systems of care, including Veterans Integrated Services Networks (VISNs). Main Outcomes and Measures Monthly receipt of any COVID-19 pharmacotherapy (nirmatrelvir-ritonavir, molnupiravir, sotrovimab, or bebtelovimab) was described. Multivariable logistic regression was used to identify factors independently associated with receipt of any vs no COVID-19 pharmacotherapy. Results Among 285 710 veterans (median [IQR] age, 63.1 [49.9-73.7] years; 247 358 males [86.6%]; 28 444 Hispanic [10.0%]; 61 269 Black [21.4%] and 198 863 White [69.6%]) who tested positive for SARS-CoV-2 between January 2022 and January 2023, the proportion receiving any pharmacotherapy increased from 3285 of 102 343 veterans (3.2%) in January 2022 to 5180 of 21 688 veterans (23.9%) in August 2022. The proportion declined to 2194 of 10 551 veterans (20.8%) by January 2023. Across VISNs, the range in proportion of patients who tested positive who received nirmatrelvir-ritonavir or molnupiravir during January 2023 was 41 of 692 veterans (5.9%) to 106 of 494 veterans (21.4%) and 2.1% to 120 of 1074 veterans (11.1%), respectively. Veterans receiving any treatment were more likely to be older (adjusted odds ratio [aOR] for ages 65-74 vs 50-64 years, 1.18; 95% CI, 1.14-1.22; aOR for ages ≥75 vs 50-64 years, 1.19; 95% CI, 1.15-1.23) and have a higher Charlson Comorbidity Index score (aOR for CCI ≥6 vs 0, 1.52; 95% CI, 1.44-1.59). Compared with White veterans, Black veterans (aOR, 1.06; 95% CI, 1.02-1.09) were more likely to receive treatment, and compared with non-Hispanic veterans, Hispanic veterans (aOR 1.06; 95% CI, 1.01-1.11) were more likely to receive treatment. Conclusions And Relevance This study found that prescription of outpatient COVID-19 pharmacotherapies in the VHA peaked in August 2022 and declined thereafter. There were large regional differences in patterns of nirmatrelvir-ritonavir and molnupiravir use.
Updated Phylogeny and Protein Structure Predictions Revise the Hypothesis on the Origin of MADS-box Transcription Factors in Land Plants
Authors: Yichun Qiu, Zhen Li, Dirk Walther, Claudia Köhler
Journal: Molecular Biology and Evolution (2023)

MADS-box transcription factors (TFs), among the first TFs extensively studied, exhibit a wide distribution across eukaryotes and play diverse functional roles. Varying by domain architecture, MADS-box TFs in land plants are categorized into Type I (M-type) and Type II (MIKC-type). Type I and II genes have been considered orthologous to the SRF and MEF2 genes in animals, respectively, presumably originating from a duplication before the divergence of eukaryotes. Here, we exploited the increasing availability of eukaryotic MADS-box sequences and reassessed their evolution. While supporting the ancient duplication giving rise to SRF- and MEF2-types, we found that Type I and II genes originated from the MEF2-type genes through another duplication in the most recent common ancestor (MRCA) of land plants. Protein structures predicted by AlphaFold2 and OmegaFold support our phylogenetic analyses, with plant Type I and II TFs resembling the MEF2-type structure, rather than SRFs. We hypothesize that the ancestral SRF-type TFs were lost in the MRCA of Archaeplastida (the kingdom Plantae sensu lato). The retained MEF2-type TFs acquired a Keratin-like domain and became MIKC-type before the divergence of Streptophyta. Subsequently in the MRCA of land plants, M-type TFs evolved from a duplicated MIKC-type precursor through loss of the Keratin-like domain, leading to the Type I clade. Both Type I and II TFs expanded and functionally differentiated in concert with the increasing complexity of land plant body architecture. The recruitment of these originally stress-responsive TFs into developmental programs, including those underlying reproduction, may have facilitated the adaptation to the terrestrial environment.
Re: Alexandre R. Zlotta, Leslie K. Ballas, Anderzej Niemierko, et al. Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis. Lancet Oncol 2023;24:669–81
Authors: Thomas Seisen, Morgan Rouprêt, Pierre Blanchard
Journal: European Urology (2023)
Letter to the Editor: NAFLD, MAFLD or MASLD? Cut the Gordian knot with “Ludwig disease”
Authors: Enzo Emanuele, Piercarlo Minoretti
Journal: Hepatology (2023)

12E Science, Via Monte Grappa, 13, I-27038 Robbio (PV), Italy 2Studio Minoretti, Oggiono (LC), Italy Correspondence Enzo Emanuele, Scientific Directorate, 2E Science, Via Monte Grappa, 13, I-27038 Robbio (PV), Italy. Email: [email protected]
Endoluminal radiofrequency ablation in patients with malignant biliary obstruction: a randomised trial
Authors: Jana Jarosova, Lea Zarivnijova, Ivana Cibulkova, Jan Mares, Peter Macinga, Alzbeta Hujova, Premysl Falt, Ondrej Urban, Jan Hajer, Julius Spicak, Tomas Hucl
Journal: Gut (2023)

Background Endoluminal radiofrequency ablation (RFA) has been promoted as palliative treatment for patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) in order to improve biliary drainage and eventually prolong survival. No high level evidence is, however, available on this technique. Design In this randomised controlled study, we compared endoluminal RFA plus stenting with stenting alone (control group) in patients with malignant biliary obstruction; metal stents were primarily placed. Primary outcome was overall survival; secondary outcomes were stent patency, quality of life and adverse events. In a superiority design, survival was assumed to be doubled by RFA as compared with 6.4 months in the control group (n=280). Results A total of 161 patients (male:female 90:71, mean age 71±9 years) were randomised before recruitment was terminated for futility after an interim analysis. Eighty-five patients had CCA (73 hilar, 12 distal) and 76 had pancreatic cancer. There was no difference in survival in both subgroups: for patients with CCA, median survival was 10.5 months (95% CI 6.7 to 18.3) in the RFA group vs 10.6 months (95% CI 9.0 to 24.8), p=0.58)) in the control group. In the subgroup with pancreatic cancer, median survival was 6.4 months (95% CI 4.3 to 9.7) for the RFA vs 7.7 months (95% CI 5.6 to 11.3), p=0.73) for the control group. No benefit was seen in the RFA group with regard to stent patency (at 12 months 40% vs 36% in CCA and 66% vs 65% in PDAC), and quality of life was unchanged by either treatment and comparable between the groups. Adverse events occurred in seven patients in each groups. Conclusion A combination of endoluminal RFA and stenting was not superior to stenting alone in prolonging survival or improving stent patency in patients with malignant biliary obstruction. Trial registration number NCT03166436 .
Atezolizumab plus Magrolimab, Niraparib, or Tocilizumab versus Atezolizumab Monotherapy in Platinum-Refractory Metastatic Urothelial Carcinoma: A Phase Ib/II Open-Label, Multicenter, Randomized Umbrella Study (MORPHEUS Urothelial Carcinoma)
Authors: Alexandra Drakaki, Thomas Powles, Aristotelis Bamias, Juan Martin-Liberal, Sang Joon Shin, Terence Friedlander, Diego Tosi, Chandler Park, Carlos Gomez-Roca, Florence Joly Lobbedez, Daniel Castellano, Rafael Morales-Barrera, Irene Moreno-Candilejo, Aude Fléchon, Kobe Yuen, Deepali Rishipathak, Kelly DuPree, Fiona Young, Francesca Michielin, Colby S. Shemesh, Elizabeth E. Steinberg, Patrick Williams, Jae Lyun Lee
Journal: Clinical Cancer Research (2023)

The MORPHEUS platform was designed to identify early efficacy signals and evaluate the safety of novel immunotherapy combinations across cancer types. The phase Ib/II MORPHEUS-UC trial (NCT03869190) is evaluating atezolizumab plus magrolimab, niraparib, or tocilizumab in platinum-refractory locally advanced or metastatic urothelial carcinoma (mUC). Additional treatment combinations were evaluated and will be reported separately.Patients had locally advanced or mUC that progressed during or following treatment with a platinum-containing regimen. The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Key secondary endpoints included investigator-assessed progression-free survival (PFS) and overall survival (OS). Safety and exploratory biomarker analyses were also conducted.Seventy-six patients were randomized to receive either atezolizumab plus magrolimab (n = 16), atezolizumab plus niraparib (n = 15), atezolizumab plus tocilizumab (n = 15), or atezolizumab monotherapy (control; n = 30). No additive benefit in ORR, PFS, or OS was seen in the treatment arms versus the control. The best confirmed ORR was 26.7% with atezolizumab plus magrolimab, 6.7% with atezolizumab plus niraparib, 20.0% with atezolizumab plus tocilizumab, and 27.6% with atezolizumab monotherapy. Overall, the treatment combinations were tolerable, and adverse events were consistent with each agent's known safety profile. Trends were observed for shrinkage of programmed death-ligand 1-positive tumors (atezolizumab, atezolizumab plus magrolimab, atezolizumab plus tocilizumab), inflamed tumors, or tumors with high mutational burden (atezolizumab), and immune excluded tumors (atezolizumab plus magrolimab).The evaluated regimens in MORPHEUS-UC were tolerable. However, response rates for the combinations did not meet the criteria for further development in platinum-experienced locally advanced or mUC.